Leptin is a hormone primarily involved in the regulation of basal metabolism and with an important role in immune responses. Leptin promotes inflammation and can accelerate onset and progression of several autoimmune diseases in mice. We have preliminary data that suggest that leptin may also play a role in the pathogenesis of murine and human systemic lupus erythematosus (SLE). Because of that, we will dissect the immune effects of leptin on human SLE and will test new possibilities of leptin-based intervention in SLE. Since we hypothesize that leptin affects the phenotype and function of immune-cell subsets and promotes the release of soluble mediators in order to exert its pro-pathogenic effects in SLE, we will study several cellular aspects (phenotype, function) and molecular events (cell signaling) induced by leptin in human SLE. We will then test different approaches of leptin-based therapeutic intervention in SLE using different leptin antagonists, first in vitro and then in vivo, to ultimately set the stage for translation studies to humans. In parallel, we will do genetic association studies to address whether leptin-related polymorphisms in SLE can contribute to a predisposing background by modulating leptin levels or responsiveness to leptin. By defining some crucial aspects related to the physiopathology of leptin in SLE, these studies will explore new strategies of therapeutic intervention for SLE that may ultimately lead to improved management of the disease. LAY DESCRIPTION OF THE PROJECT: Leptin is a hormone that controls several functions in humans, including immune responses. We have preliminary data that suggest that leptin can play an important role in the development and progression of systemic lupus erhytematosus, an incurable disease that is characterized by systemic effects and by the production of antibodies to self components that cause irreversible kidney damage. This study will detail the effects of leptin on human lupus and compare the potential of different leptin-based approaches with the goal to improve the current therapeutic management of human lupus.